The evolutionary landscape of colorectal tumorigenesis
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ABSTRACT:
PROVIDER: EGAS00001003066 | EGA |
REPOSITORIES: EGA
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Project description:Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and therefore provide novel opportunities for the molecular analysis of tumors. We have now analyzed DNA methylation patterns in colorectal adenomas and identified three biologically defined subclasses that describe different intestinal crypt differentiation stages. Importantly, colorectal carcinomas could be classified into the same methylation subtypes, reflecting their shared cell-types of origin with adenomas. Further data analysis also revealed significantly reduced overall survival for one of the subtypes. Our results establish a novel concept for understanding the methylation patterns observed in colorectal cancer and provide opportunities for tumor subclassification and patient stratification.
2018-06-12 | E-MTAB-6450 | biostudies-arrayexpress
Project description:Chromosomal instability (CIN) is the hallmark of colorectal adenoma to carcinoma progression in 85% of cases, with 20q gain as the most prominent aberration. Yet, the oncogenes at this chromosomal gain are still largely unknown. Here, we aimed to identify oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on gene expression in this amplicon. Segmentation of DNA copy number changes on 20q was performed by array CGH in 67 colorectal adenomas and carcinomas. Additionally, robust analysis of mRNA expression in these segments was performed in 68 adenomas and carcinomas. This approach revealed seven genes to be important in CIN related adenoma to carcinoma progression. These genes may both serve as highly specific biomarkers for presence of high-risk precursor lesions as well as potential targets for pharmaceutical intervention. Keywords: Integration of array CGH and expression microarrays in colorectal cancer progression We performed array CGH on a panel of 41 progressed adenomas, from which the adenoma and carcinoma components were separately analysed (total, 82 samples). The DNA obtained from these samples was extracted from formalin-fixed, paraffin-embedded material. Additionally we analysed a series of independent frozen adenomas and carcinomas by array CGH (34 adenomas and 33 carcinomas) and expression microarrays (37 adenomas and 31 carcinomas). For array-CGH we used as reference DNA for all samples, a pool of 10 normal individuals. For expression microarrays we used as reference a commercial available RNA (pool of different cancer cell lines), from Strategene. No replicates nor dye swaps were done.
2010-06-25 | E-GEOD-8067 | biostudies-arrayexpress
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.
2011-04-19 | E-GEOD-21392 | biostudies-arrayexpress
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2018-12-31 | GSE121142 | GEO
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer.
2011-04-19 | GSE21392 | GEO
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2015-11-25 | GSE75415 | GEO
Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. Here we show Human SNP 6.0 Array experiments on DNAs from four colorectal cancer patients (1BV, 2BV, 3BV, and 4BV) with polyps and metastases. Here we characterize the samples for CNVs and compare the samples' CNV status to their respective somatic L1 retrotransposition profile.
2015-08-10 | E-GEOD-63601 | biostudies-arrayexpress
Project description:Chromosomal instability (CIN) is the hallmark of colorectal adenoma to carcinoma progression in 85% of cases, with 20q gain as the most prominent aberration. Yet, the oncogenes at this chromosomal gain are still largely unknown. Here, we aimed to identify oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on gene expression in this amplicon. Segmentation of DNA copy number changes on 20q was performed by array CGH in 67 colorectal adenomas and carcinomas. Additionally, robust analysis of mRNA expression in these segments was performed in 68 adenomas and carcinomas. This approach revealed seven genes to be important in CIN related adenoma to carcinoma progression. These genes may both serve as highly specific biomarkers for presence of high-risk precursor lesions as well as potential targets for pharmaceutical intervention. Keywords: Integration of array CGH and expression microarrays in colorectal cancer progression
2008-10-15 | GSE8067 | GEO
Project description:Colorectal adenomas are common precancerous lesions with the potential for malignant transformation to colorectal adenocarcinoma. Endoscopic polypectomy provides an opportunity for cancer prevention, however, recurrence rates are high. We collected formalin-fixed paraffin-embedded tissue of fourteen primary adenomas with recurrence, fourteen primary adenomas without recurrence, and fourteen matched pair samples (primary adenoma and the corresponding recurrent adenoma). These samples were analysed by array-based comparative genomic hybridisation (aCGH) to understand the dynamics of copy number alterations (CNAs) and to identify molecular markers to predict recurrence. ACGH analysis confirmed the genetic landscape specific for colorectal tumorigenesis, i.e., CNAs of chromosomes 7 (13.7%), 13q (13.7%), 18 (5.8%) and 20q (13.7%). CNAs were detected in 41/51 (80.4%) of colorectal adenomas (2N). Focal aberrations (≤10 Mbp) were mapped to chromosome bands 6p22.1-p21.33 (33.3%), 7q22.1 (31.4%) and 16q21 (29.4%). Gains of CDX2 were exclusively seen in adenomas with recurrence compared to adenomas without recurrence. However, the average number of copy alterations failed to discriminate primary adenomas with recurrence from primary adenomas without recurrence.
2018-04-01 | GSE110221 | GEO